The effect of Sailuotong (SLT) on neurocognitive and ......dementia [13]. For example, acetylcholinesterase (AChE) inhibitors (e.g., donepezil) act on the enzyme which breaks down

RESEARCH ARTICLE Open Access

The effect of Sailuotong (SLT) onneurocognitive and cardiovascular functionin healthy adults: a randomised, double-blind, placebo controlled crossover pilottrialGenevieve Z. Steiner1,2†, Alan Yeung1†, Jian-Xun Liu3, David A. Camfield4,5, Frances M. de Blasio2,Andrew Pipingas4, Andrew B. Scholey4, Con Stough4 and Dennis H. Chang1*

Abstract

Background: Sailuotong (SLT) is a standardised herbal medicine formula consisting of Panax ginseng, Ginkgo biloba,and Crocus sativus, and has been designed to enhance cognitive and cardiovascular function.

Methods: Using a randomised, double-blind, placebo controlled crossover design, this pilot study assessed theeffect of treatment for 1 week with SLT and placebo (1 week washout period) on neurocognitive and cardiovascularfunction in healthy adults. Sixteen adults completed a computerised neuropsychological test battery (Compass), andhad their electroencephalographic (EEG) activity and cardiovascular system function assessed. Primary outcomemeasures were cognitive test scores and oddball task event-related potential (ERP) component amplitudes.Secondary outcome measures were resting EEG spectral band amplitudes, and cardiovascular parameters.

Results: Treatment with SLT, compared to placebo, resulted in small improvements in working memory, a slightincrease in auditory target (cf. nontarget) P3a amplitude, and a decrease in auditory N1 target (cf. nontarget)amplitude. There was no effect of SLT on EEG amplitude in delta, theta, alpha, or beta bands in both eyes openand eyes closed resting conditions, or on aortic and peripheral pulse pressure, and resting heartrate.

Conclusions: Findings suggest that SLT has the potential to improve working memory performance in healthyadults; a larger sample size is needed to confirm this.

Trial registration: Australia New Zealand Clinical Trials Registry Trial Registration Id: ACTRN12610000947000.

Keywords: Sailuotong (SLT), Chinese Herbal Medicine (CHM), EEG, Event-related potentials (ERPs), P3(00), Bloodpressure, Heartrate (HR), Neurocognition, Age related cognitive decline

BackgroundMost individuals experience a normal age-related declinein a range of cognitive abilities including a decrease in in-formation processing speed, and learning and memoryabilities [1]. For instance, cross-sectional studies havedemonstrated that working memory ability decreases

across most of the adult lifespan, with sharper declinesafter 70 years of age [2]. Management of age-relatedchanges in cognition can be challenging as symptoms canclosely overlap with early stages of dementia, such as Alz-heimer’s disease, which has a different pathophysiology;for example, the presence of neurofibrillary tangles andbeta-amyloid plaques [3].The ageing process can also be associated with neuro-

logical pathology [4], particularly at a cellular level. For in-stance, a loss of synaptic density can contribute to areduction in regional brain volume and cortical thickness

* Correspondence: [email protected]†Equal contributors1National Institute of Complementary Medicine, and School of Science andHealth, Western Sydney University, Penrith NSW 2751, AustraliaFull list of author information is available at the end of the article

© 2016 Steiner et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Steiner et al. BMC Complementary and Alternative Medicine (2016) 16:15 DOI 10.1186/s12906-016-0989-0

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[5–7], with some regions that are responsible for advancedcognition (e.g., working memory), including the prefrontalcortex, showing a steady decline after the age of 20 [1].Other factors linked to age-related cognitive decline (andpossibly the pathogenesis of dementia) include changes inbrain metabolite concentrations, inflammation, oxidativestress, brain vascular integrity, and poor circulation, whichmay be associated with a number of disease-related andlifestyle-related risk factors such as diabetes, cardiovascu-lar disease, obesity, and excessive alcohol consumption[8–12].In order to minimise the functional impairment asso-

ciated with the ageing process, particularly slowing,stabilising, or (possibly) reversing cognitive decline, thereis a demand for appropriate pharmacological interven-tions. Currently, there are few pharmaceutical optionsavailable for otherwise healthy individuals, and these areusually prescribed under the assumption of a patho-physiological relationship between cognitive decline anddementia [13]. For example, acetylcholinesterase (AChE)inhibitors (e.g., donepezil) act on the enzyme whichbreaks down acetylcholine, increasing its availability inthe synapses [14]; and N-methyl-D-asparate (NMDA)glutamate receptor antagonists (e.g., memantine) nor-malise the glutamatergic system by blocking NMDAglutamate receptors [15]. There is little evidence tosuggest that these pharmacological approaches caneffectively treat forms of cognitive decline other thandementia, including mild cognitive impairment [16–18]which is often considered the prodromal phase forAlzheimer’s disease [13]. AChE inhibitors are alsopoorly tolerated, with adverse side effects related to cho-linergic hyperactivity including bradycardia, hypotension,gastrointestinal disturbances, vomiting, and bronchocon-striction [19], making their implementation ethically un-sound in populations that are otherwise unimpaired [20].Further, the global changes associated with age-relatedcognitive decline mentioned above indicate the need formulti-target [21], rather than single-target treatments.Where standard pharmaceuticals often utilise a single-

target approach (e.g., AChE inhibitors), complementarymedicine treatments, such as Chinese Herbal Medicine(CHM), apply a multisystem approach in which combin-ation multi-target therapies are used to treat disease[22]. Complex herbal formulations used in CHM canalso have a synergistic effect, where additional extrac-tions increase the efficacy of the formula as a whole[23–27]. Given this approach, CHM may be more suit-able in the treatment of age-related cognitive decline,and is well-suited for chronic interventions due to accu-mulative effects on multiple systems over a period oftime. Further, early research suggests that some herbalformulations can enhance memory function and increaselongevity [28].

Sailuotong (SLT) is a new standardised three-herbformula that combines specific doses of the key bioactiveconstituents from the concentrated extracts of Panaxginseng (ginsenosides), Ginkgo biloba (flavone-glyco-sides), and Crocus sativus (crocins), and has been devel-oped to enhance cognitive and cardiovascular functionthrough multiple pathways of action based on a compre-hensive review of the CHM and medical literature. Thethree herbal constituents have each demonstrated neu-roprotective, antioxidant, and anti-hypertensive prop-erties [29–32], and preliminary research suggests thepossibility of an enhanced therapeutic effect due tosynergism [23–25].Preclinical pharmacokinetic, pharmacodynamic, and

toxicity studies have been conducted on these threeherbs separately, and in combination [29–38]. Treatmentwith SLT in various experimental ischemia and amnesiamodels in rodents resulted in improved learning andmemory function, antioxidant capacity, and pathogenicbiochemical blood and brain tissue parameters. Forexample, over an eight week period, SLT decreased thelatency for finding the platform in a Morris Water Mazein rats with chronic cerebral hypoperfusion modelinduced by bilateral common carotid artery ligation [35].Brain tissue cholinesterase decreased and acetylcholinelevels increased, and importantly, superoxide dismutase(an enzyme that acts as an antioxidant) also increased.In a similar investigation using an amyloid beta-proteininduced dementia model in mice [36], brain tissueacetylcholine increased by 18.56 and 19.97 %, respect-ively, when treated for 30 days with low (15.5 mg/kg)and high (31.0 mg/kg) doses of SLT. Another studyusing a PDAPPv7171 transgenic dementia model in miceshowed that treatment for 12 weeks with both low(31 mg/kg) and high (62 mg/kg) doses of SLT increasedbrain tissue acetylcholine levels [31]; brain tissue sero-tonin levels decreased in the high dosage group only.A range of cardiovascular benefits of SLT have also

been demonstrated [29, 30, 33]. Acute treatment over24 h decreased the areas of focal cerebral ischemia/re-perfusion injury in mice, and increased cerebral bloodflow was also observed 60–180 min after administration(10 mg/kg) [33]. Rats also showed a decrease in plateletaggregation rate and whole blood viscosity after treat-ment with low (8 mg/kg) and high (16 mg/kg) doses ofSLT for 7 days.In humans, a 16 week pilot study of SLT was

conducted on individuals with probable or possiblevascular dementia [38]. Participants treated with SLTshowed a significant improvement in Alzheimer’s Dis-ease Assessment Scale cognitive subscale (ADAS-cog)scores compared to placebo. Participants also reportedsignificant improvements in quality of life (Short FormHealth Survey; SF-36) related to emotional and physical

Steiner et al. BMC Complementary and Alternative Medicine (2016) 16:15 Page 2 of 13

role functioning, mental health, and social functioning.A subset of participants also underwent single photonemission computed tomography (SPECT) scan, whichdemonstrated that those treated with SLT, compared toplacebo, showed increased blood flow in the inferiorfrontal and anterior temporal lobes, which was greaterin the left hemisphere. This is a particularly promisingfinding, as those regions are associated with memoryfunction, and auditory and speech processing.Due to the lack of treatment options available for age-

related cognitive decline, and SLT’s potential to improvecognitive and cardiovascular function, a trial of SLT onhealthy individuals is warranted. The current pilot studyemployed a randomised, double-blind, placebo controlledcrossover design, and aimed to provide preliminary dataon the possible cognitive and cardiovascular benefits ofSLT in healthy adults. Neurocognitive function wasassessed using a computerised cognitive test battery, odd-ball task event-related potential (ERP) component ampli-tudes, and resting EEG spectral band amplitudes.Cardiovascular system function measures were centraland peripheral pulse pressure, and resting heartrate (HR).It was hypothesised that treatment for 1 week with SLTwould improve neurocognitive and cardiovascular func-tion compared to placebo.

MethodsInclusion criteriaSixteen adults were recruited from students, staff, andtheir families at Western Sydney University through ad-vertisements on campus. All provided informed consentand were advised that they were free to withdraw at anytime without penalty. Participants were excluded if theywere pregnant, obese (to reduce the chance of recruitingparticipants with associated chronic diseases), had a his-tory of allergies, serious gastrointestinal disorders,asthma or serious pulmonary disorders, diabetes, or anysignificant abnormality on laboratory tests including fullblood count, liver, and renal function. Any participantstaking anti-coagulant or cognitive enhancing medica-tion/substances, including over the counter Ginkgobiloba or Panax ginseng capsules, were also excluded.All participants were non-smokers and showed no signsof neurological impairment (mini mental state exam;MMSE > 28).

TreatmentsSLT treatment: SLT formula is standardised by the bio-active components of the three herbal extracts fromPanax ginseng, Ginkgo biloba, and Crocus sativa. Arange of in vivo pharmacological studies have beenundertaken to test the bioactivity and determine theoptimal ratio of the three individual herbal extracts.Each SLT capsule contains a 60 mg standardised mixture

of 27.27 mg ginsenosides from Panax ginseng, 27.27 mgtotal ginkgo flavone-glycosides from Ginkgo biloba, and5.46 mg crocins from Crocus sativa. The SLT prepara-tions were manufactured in a Good Manufacturing Prac-tice certified facility.Placebo: Two capsules per day, containing an inert sub-

stance matched for the colour, taste, and smell of SLT.

DesignThis pilot study employed a randomised, placebo con-trolled, double-blind crossover design. Participants wererequired to orally ingest two capsules of either SLT or aplacebo every day for one week. This was followed by aone week washout period and the subsequent counter-balanced treatment week. This washout period lengthwas determined by preclinical pharmacokinetic studies[33]. The active herbal formulation and placebo wereprepared in an extract capsule form in accordance withAustralian Goods Manufacturing Practices. Neurocogni-tive and cardiovascular function were tested before andafter each of the interventions. Primary outcome mea-sures included neurocognitive function test scores,and ERP component amplitudes. Secondary outcomemeasures were EEG spectral band amplitudes, aorticand peripheral pulse pressure, and resting HR. Theprocedure was approved by Western Sydney Universi-ty's Human Research Ethics Committee (Ethics Ap-proval: H8253), and the trial was registered with theAustralian New Zealand Clinical Trials Registry (TrialId: ACTRN12610000947000).

Materials and apparatusCognitive test batteryCognitive function was tested using the ComputerisedMental Performance Assessment System (Compass)neuropsychological test battery, which measures a rangeof cognitive abilities including attention, episodic mem-ory, and working memory. These cognitive domainswere assessed using 12 Compass tasks: Immediate WordRecall, Delayed Word Recall, Word Recognition, SimpleReaction Time, Choice Reaction Time, Numeric Work-ing Memory, Alphabetic Working Memory, Corsi BlockSpan, N-Back Working Memory, Picture Recognition,Face Recognition, Serial Subtraction, and Rapid VisualInformation Processing (RVIP). Parallel versions of eachtask were used for the repeated testing sessions.Mental fatigue and Mood were self-reported on a

Visual Analogue Scale (VAS) using a 100 mm horizontalline displayed on a computer monitor, with each end-point marking the two extremes of mental fatigue ormood; participants responded using a computer mousecursor. Three dimensions of mood were assessed (alert-ness, calmness, and contentment) with 16 separateBond-Lader VAS items [39].


https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335920&isReview=true

Electroencephalograph (EEG)EEG data were recorded continuously from 18 scalpsites (F1, F3, Fz, F2, F4, C1, C3, Cz, C2, C4, P1, P3, Pz,P2, P4, O1, Oz, O2) with a 64 channel electrode capusing sintered Ag/AgCl electrodes. The nose was usedas a reference and the cap was grounded by an electrodelocated midway between AF3 and AF4. Data wereacquired 0–200 Hz using a Neuroscan Synamps 2 digitalsignal-processing system and Neuroscan 4.3.1 Acquiresoftware. The display and stimulus markers were con-trolled by a separate stimulus computer (Dell Optiplex760 with a 22 " LG Flatron W2253TQ screen) usingCompumedics Stim2 (4.0.09302005) software.Electro-oculogram (EOG) was recorded using sintered

Ag/AgCl electrodes placed 2 cm above and below theleft eye for vertical movements, and on the outer can-thus of each eye for horizontal movements. Impedancewas less than 10 kΩ for cap, EOG, and reference elec-trodes. Scalp and EOG potentials were amplified with again of 2816 and digitised at 1000 Hz.EEG was recorded during two resting conditions

(5 min eyes open and 5 min eyes closed) followed bytwo oddball tasks (visual then auditory). For the visualoddball task, stimuli were white 37 × 43 mm letters(target: X; nontarget: O) presented for 500 ms on a blackbackground. For the auditory task, acoustic stimuli weredelivered binaurally through foam stereo eartips (ER3-15A) using the Stim Audio System (P/N 1105), and con-sisted of 1000 Hz (target) and 500 Hz (nontarget) 80 dBtones (500 ms duration, 10 ms rise/fall time). For eachof these tasks, a randomised stimulus sequence consistingof 200 trials was presented (target p = .2, nontarget p = .8)with an ISI of 1.5 s in a single block that wasapproximately 5 min in duration. Targets were respondedto with a button press using the Stim System SwitchResponse Pad (P/N 1141).

Cardiovascular measuresAortic and peripheral measures of pulse pressure, andresting HR were assessed using an electronic sphygmo-manometer and tonometer (AtCor Medical Sphygmo-Cor CVMS v8.2); the mean across three consecutivemeasurements of each index was computed. To ensurereliability, only measurements equal to or greater thanan Operator Index of 80 were used. The OperatorIndex is a measure of quality control derived from themean and variability in pulse strength, diastolic vari-ation, and systolic shape deviation. The score is out of apossible 100, and an Index over 80 is consideredacceptable.

ProcedureParticipant eligibility was confirmed during a brieftelephone interview. Then, during a screening session,

participants provided informed consent and completedthe MMSE before a medically trained professional con-ducted a medical questionnaire, physical examination,and provided participants with a pathology requestform so that blood samples could be taken and analysedat a Douglas Hanley Moir pathology laboratory. Bloodsampling was only deemed necessary for participantsaged 50–75; pathology examined were full blood count,and liver and kidney function. If no abnormalities werediscovered participants completed a training session onthe Compass test battery, and were randomly allocatedto a treatment group via a computer randomisationpackage. The randomisation was conducted by the re-search program coordinator externally to the researchteam and the assignments were blinded to all investiga-tors and assessors as well as to the trial participants.All data were collect at the National Institute ofComplementary Medicine Clinical Laboratory, WesternSydney University during 2012–2013.At the beginning of each of the one-week interven-

tion cycles, participants attended a baseline sessionwhere they were asked a series of questions about anyillnesses or adverse events, and whether they hadstarted, stopped, or changed any medications. Then,whilst sitting comfortably, participants had their cardio-vascular measurements taken, completed the Compasstesting battery, were fitted with EEG recording appar-atus, and had their EEG activity recorded. Each of thesebaseline sessions ran for approximately 2.5 h. Effortswere made to ensure that each timepoint for eachparticipant was at the same time of day. Participantswere dispensed eighteen capsules containing either theSLT formulation or placebo (depending on randomisa-tion) and were instructed to take two capsules per dayfor one week (morning and night with food), and to re-turn any unused capsules at the post-treatment session.Four extra capsules were provided in the event thatparticipants were unable to attend the next scheduledappointment. Halfway through the treatment cycle, abrief telephone follow-up was conducted to ensureparticipant safety in regards to adverse reactions andillness, and to confirm the time and date of the nexttesting session. The post-treatment sessions were iden-tical to the baseline, with the exception that partici-pants returned any excess capsules and also completeda short survey to determine the successfulness of theblinding procedure.After the initial intervention cycle, there was a seven

day washout period to allow for the elimination of anyresidual herbal compound from the body. Following this,participants began a second week of treatment in whichthey received the counterbalanced treatment condition(SLT or placebo), and again were tested pre- and post-intervention cycle.


EEG data extraction and quantificationUsing Neuroscan Edit software (Compumedics, Ver-sion 4.3.1), the EEG data were EOG artefact [40] andDC-offset corrected, and low-pass filtered at 30 Hz(24 dB/Octave). Any additional artefacts exceeding ±100 μV were excluded. Oddball task data were epochedfrom 200 ms pre- to 1400 ms post-stimulus and base-line corrected using the pre-stimulus period. Trialscontaining omission (misses) and commission (falsealarms) errors were excluded. For each subject andeach modality, averages were computed for each of thefour treatment sessions and the two stimulus condi-tions. Averaged half-sampled data (epoched −100 to600 ms: 350 datapoints) from 18 scalp locations weresubmitted to two separate temporal Principal Compo-nents Analyses (PCAs; one for each modality) usingthe ERP PCA toolkit (v. 2.23 [32]) in MATLAB (TheMathsworks; Version 8.0.0.783, R2012b). In each of thePCAs, factors for all conditions were quantified simultan-eously (2304 observations: 16 participants × 2 stimulusconditions × 4 testing sessions × 18 electrodes). ThePCAs used the unstandardised covariance matrix withKaiser normalisation, and all 350 unrestricted factorsunderwent Varimax rotation [41]. PCA factors wereidentified as ERP components based on their latency,topography, and polarity of their conspicuous max-imum loading. The peak amplitude of each identifiedcomponent was output and entered into subsequentstatistical analyses.The 5 min of artefact-corrected data from each of the

resting conditions were epoched to 2000 ms and thenquantified in MATLAB and EEGLAB (Version 9.0.8.6b[42]). For each subject and each condition, spectral am-plitudes were computed using discrete Fast FourierTransforms with a 10 % Hanning window for each ofthe four treatment sessions. Frequency data from 0 to30 Hz were extracted with a resolution of 0.5 Hz, beforeaveraging across epochs. The spectral band amplitudeswere calculated by summing the activity across the fre-quency bins for delta 0.5-3.5 Hz, theta 4.0-7.5 Hz, alpha8.0-13.0 Hz, and beta 13.5-29.5 Hz.

Statistical analysesAs this was a pilot trial, no formal sample size calcula-tion was made. Sample size was approximated based ona trial [65] which employed two of the three SLT constit-uents as a combined intervention using a similar cross-over design. A post-hoc sample size calculation showedthat in order to detect a difference of d = 1.00 at 80 %power, two-tailed, α = .05, 17 participants were required,suggesting that the sample size used here, althoughsmall, was sufficient to detect a meaningful change inthe primary outcome measure.

Cognitive and cardiovascular measuresRelevant outcome measures were recorded automaticallyby the Compass and SphygmoCor software. Separaterepeated measures analyses of variance (ANOVAs) withTreatment (SLT vs. placebo) and Time (baseline vs. post-treatment) as within-subject factors was used to com-pare the effects of SLT with placebo for each of theCompass and cardiovascular measures. As this was apilot study, results approaching significance (p < .10) arereported as they may potentially reflect the existence ofreal effects.

EEG and ERPsExpected EEG band and ERP component topographieswere defined by selecting a cluster of electrodes sur-rounding the site of maximal amplitude. Using a meanacross a region defined by multiple sites, rather than asingle electrode, reduces the impact of chance varianceat a single site [43].Separate repeated-measures MANOVAs then assessed

each band and component’s amplitude for the effects ofCondition (EEG: eyes open vs. eyes closed; ERPs: targetvs. nontarget), Treatment (SLT vs. placebo) and Time(baseline vs. post-treatment). Cohen’s d effect sizes arereported. The violations of sphericity assumptions asso-ciated with repeated-measures analyses do not affectsingle degree of freedom contrasts, so Greenhouse-Geisser-type correction was not necessary [44]. All F-tests reported have (1, 15) degrees of freedom.One-way tests were utilised for all analysed predic-

tions. It should also be noted that, as this paper detailsresults for a number of dependent measures, thefrequency of Type I errors increases. However, this in-crease in frequency of Type I errors cannot be con-trolled by adjusting α-levels, because the probability ofType I error remains the same [45].

ResultsAs shown in Fig. 1, a total of 39 individuals expressedinterest in the trial with 17 individuals randomised and22 excluded due to failure to meet inclusion/exclusioncriteria or availability constraints. Demographics andclinical characteristics of the 16 participants thatcompleted the trial are presented in Table 1.

Cognitive functionTable 2 displays the mean and standard error across sub-jects before and after treatment with SLT and placebofor each of the Compass tasks, together with measuresof fatigue and alertness. Two of the Compass tasksshowed effects of SLT that approached statistical signifi-cance. For the Alphabetic Working Memory Task, adecrease in reaction time from baseline to post-treatment was larger for SLT than placebo (F = 3.72,


p = .073, d = 1.00). SLT also enhanced N-Back task per-formance, with greater accuracy reported after treatment(cf. baseline) with SLT than placebo (F = 4.35, p = .054,d = 1.09). The other Compass tasks and VAS mood andalertness scales did not show an effect of SLT (no treat-ment × time interaction).

ERP componentsFigure 2 illustrates the grand mean ERPs for targets andnontargets (solid lines) from midline sites (left: visual;right: auditory).For the visual task PCA, factors 1–4 and factor 6

accounted for 84.9 % of the total variance, and for theauditory task PCA, the first 5 accounted for 87.8 % ofthe variance; these factors were extracted and retainedfor analysis. The sum of these extracted factors is illus-trated in Fig. 2 (dashed lines) for each modality. Whencorrelated across the midline, the reconstructed and ori-ginal waveforms were highly similar for visual targets,r(1048) = .97, p = < .001, and nontargets, r(1048) = .92,p = < .001, and for auditory targets, r(1048) = .99, p = <.001, and nontargets, r(1048) = .98, p = < .001.For each modality, the temporal factor loadings

(rescaled to μV by multiplying each time point by thestandard deviation [46]) for each of the ERP componentsare displayed as a function of time in Fig. 3. Topographicheadmaps of the temporal components, averaged acrosstreatment, time, and stimulus condition are displayed

above the factor loadings for each of the modalities.Component labels, site of maximal amplitude, percent-age of variance explained, and sites selected for analysisfor each of the rotated components are indicated inTable 3. Components were labelled according to theirpolarity, latency, temporal sequence, comparison withthe raw ERPs (see Fig. 2), and topography.Table 4 details the mean and standard error across sub-

jects for each analysed visual (middle) and auditory(lower) ERP component (targets and nontargets), at base-line and post-treatment, for both SLT and placebo. Asshown in Table 4, amplitudes were significantly greater fortargets than nontargets for visual N1 (F = 20.70, p < .001,d = 2.35), N2 (F = 20.60, p < .001, d = 2.35), and P3b(F = 34.26, p < .001, d = 3.06). There were no effects or

Fig. 1 Flow chart of the study participants

Table 1 Baseline demographics and clinical characteristics ofparticipants

Demographics Mean ± Standard Deviation

Age (years) 49.19 ± 14.28

Height (cm) 169.29 ± 9.35

Weight (kg) 70.50 ± 18.56

MMSE 29.50 ± 0.60

Pulse (bpm) 68.82 ± 14.27

Blood Pressure Systolic (mmHg) 118.71 ± 19.02

Blood Pressure Diastolic (mmHg) 76.29 ± 9.80


interactions involving treatment and time for any ofthe visual ERP components.Table 4 also illustrates significantly larger amplitudes

to targets than nontargets for auditory N2 (F = 17.14,p = .001, d = 2.12), P3a (F = 10.61, p = .005, d = 1.67),and P3b (F = 88.73, p < .001, d = 4.96). As shown inFig. 4, auditory target N1 was smaller following SLT com-pared to placebo (from baseline to post-treatment) thannontarget N1 (F = 6.39, p = .023, d = 1.31). For auditoryP3a, the target enhancement showed a greater increaseafter treatment (cf. baseline) with SLT in comparison toplacebo that approached significance (F = 3.15, p = .096,d = 0.91; see Fig. 4). Topographic headmaps (Fig. 4)illustrate that these differences were largest centrallyand on the left. There were no other treatment × timeinteractions for the other auditory ERP components.

EEG spectral bandsDelta and theta had a strong midline topography (definedas mean across Fz, Cz, Pz), and alpha and beta were bothlargest at parietal sites (mean across P3, Pz, P4). Theacross-subjects means and standard errors for each of theEEG bands, before and after both treatments, are detailedin Table 4, separately for eyes open and eyes closed condi-tions. Table 4 shows that amplitudes were greater for eyesclosed than eyes open for both theta (F = 17.92, p = .001,d = 2.17) and alpha (F = 5.43, p = .034, d = 1.22) bands.There were no significant main effects or interactions fordelta or beta. Treatment with SLT did not affect restingEEG amplitude for any of the four bands.

Table 2 Mean difference and standard error between the SLTand placebo treatments for each Compass task

Compass Task Mean Difference ± StandardError

Immediate Word Recall (number correct) 0.19 ± 0.04

Delayed Word Recall (number correct) 0.69 ± -0.03

Word Recognition (number correct) -0.06 ± 0.24

Picture Recognition (number correct) -0.5 ± 0.23

Face Recognition (number correct) 0.31 ± -0.11

Simple Reaction Time (ms) 6.07 ± 7.54

2 Choice Reaction Time (accuracy %) -0.88 ± 0.59

2 Choice Reaction Time (ms) 21.36 ± 11.82

4 Choice Reaction Time (accuracy %) 0.26 ± -0.18

4 Choice Reaction Time (ms) -18.68 ± 0.68

Numerical Working Memory (accuracy %) 3.34 ± -1.12

Numerical Working Memory (ms) 90.09 ± 60.33

Alphabetic Working Memory (accuracy %) 0.13 ± -1.09

Alphabetic Working Memory (ms) -44.14 ± -19.78

Corsi Block Span (Span Length) 0.25 ± -0.01

N-Back (accuracy %) 4.17 ± -0.82

Serial Subtract 3 (number correct) 1.63 ± -0.82

Serial Subtract 7 (number correct) -0.94 ± -0.27

Rapid Visual Information Processing(accuracy %)

-2.16 ± 0.13

Rapid Visual Information Processing (ms) 40.67 ± -16.79

Mental Fatigue (End - Start) -0.63 ± -2.32

Alertness (End - Start) 1.89 ± 0.40

Note: Tasks that are bolded had a treatment × time interaction thatapproached statistical significance (p < .10)

Fig. 2 Grand mean ERPs for targets and nontargets from the midline sites for both visual (left) and auditory (right) modalities. The solid lines representthe raw data, and the dashed lines illustrate the reconstructed PCA waveforms. PCA extracted components are labelled at Fz for both modalities


Fig. 3 Factor loadings for visual (top) and auditory (bottom) modalities. The topographic headmaps for each of the extracted ERP componentsare shown above the factor loadings (averaged across all subjects, treatments, and testing sessions), separately for each modality

Table 3 Information for the factors identifiable as ERP components

Visual TF004 TF006 TF002 TF003 TF001

Component N1 P2 N2 P3a P3b

Latency (ms) 168 208 252 352 420

Maximal Site P3 O2 P4 P1 C2

Variance (%) 3.8 2.5 16.6 16.3 45.8

Sites Analysed P3, P4 Fz C3, Cz, C4 Fz, Cz, P3, Pz, P4 Cz, Pz

Auditory TF005 TF004 TF002 TF003 TF001

Component N1 P2 N2 P3a P3b

Latency (ms) 132 210 264 348 412

Maximal Site F2 Cz Fz Fz Pz

Variance (%) 4.7 6.6 10.9 8.3 57.4

Sites Analysed F3, Fz, F4, Cz Fz, Cz F3, Fz, F4, C3, Cz, C4 F3, Fz, F4 P3, Pz, P4

Note: Rows indicate component name, latency, site of maximal amplitude, percentage of total variance explained, and sites selected for analysis.TF = Temporal Factor


Cardiovascular measuresMean peripheral and aortic pulse pressure (mmHg;systolic minus diastolic difference), and HR (bpm) forplacebo and SLT at baseline and post-treatment aredetailed in Table 5. Treatment with SLT compared to

placebo did not affect any of the three cardiovascularmeasures.

Adverse effectsNo serious adverse events were noted in this study.Minor adverse events outlined in Table 6 were notedduring each cycle of the trial. One participant with-drew from the trial during the first intervention-cycledue to mild gastrointestinal symptoms which coincidedwith a probably unrelated upper respiratory infection.Symptoms were rated as moderate severity, onset wasnoted after two doses, and duration was three to fourdays. The participant was found to be treated with theplacebo suggesting that these effects were unrelated tothe trial.

DiscussionThis pilot study investigated the effect of SLT on neuro-cognitive and cardiovascular functioning in healthyadults. Participants were assessed before and after oneweek of treatment with 2 capsules of SLT (60 mg stan-dardised extract per capsule) and placebo per day, sepa-rated by a one week washout period. Primary outcome

Table 4 Mean difference and standard error between the SLTand placebo treatments for each EEG band and ERP component(all μV)

Mean Difference ± Standard Error

EEG Spectral Band Eyes Open Eyes Closed

Delta -1.64 ± -0.01 -0.07 ± -0.73

Theta -0.82 ± -0.37 0.20 ± -0.32

Alpha -0.16 ± 0.44 -3.66 ± -0.94

Beta 2.14 ± 0.82 -0.65 ± -0.5

Visual ERP Component Target Nontarget

N1 -1.72 ± -0.06 -0.45 ± -0.17

P2 -0.37 ± -0.08 -0.69 ± 0.02

N2 -0.74 ± -0.06 -0.05 ± -0.26

P3a 2.58 ± 0.02 1.98 ± -0.20

P3b -1.12 ± 0.10 -1.38 ± -0.04

Auditory ERP Component Target Nontarget

N1 2.14 ± 0.11 -1.38 ± -0.14

P2 1.16 ± 0.84 -1.02 ± -0.31

N2 -0.14 ± 1.78 -0.04 ± -0.13

P3a 3.65 ± 0.07 -0.36 ± -0.08

P3b 0.58 ± -0.25 -2.27 ± 0.10

Note: The bolded ERP components had a treatment × time × stimulus typeinteraction (p < .10)

Fig. 4 Mean difference topographic headmaps for auditory N1 and P3a. Headmaps illustrate the difference in stimulus condition (target minusnontarget) and the difference between sessions (post-treatment minus baseline) for placebo and SLT. A SLT related reduction in N1 negativity,and an increase in P3a positivity are apparent

Table 5 Mean difference and standard error between the SLTand placebo treatments for each of the three cardiovascularmeasures

Mean Difference ± Standard Error

Peripheral Pulse Pressure (mmHg) -1.20 ± 0.52

Aortic Pressure (mmHg) -2.50 ± 0.19

Resting HR (bpm) 1.07 ± 1.55


measures were scores on a computerised neuropsycho-logical test battery, and oddball task ERP componentamplitudes. Secondary outcome measures were restingEEG band amplitudes and cardiovascular measures ofcentral and peripheral pulse amplitude, and resting HR.There was a trend towards improvements in alphabeticworking memory and visual working memory with SLTcompared to placebo. Auditory P3a amplitudes wereslightly larger following SLT than placebo for targetscompared to nontargets, and a similar target enhance-ment showed a decrease following SLT for auditory N1.SLT did not significantly affect resting state EEG activityor cardiovascular system function.On the Compass neuropsychological test battery, reac-

tion time on the Alphabetic Working Memory Task andaccuracy on the N-Back task both showed modest im-provements following treatment with SLT, compared toplacebo, suggesting that SLT may have the potential toimprove working memory performance in healthy adults.Previous work has indicated that two of the constituentsof SLT, Ginkgo biloba and Panax ginseng, have a similareffect on memory, with a large study (N = 256) showingsignificant improvements in numerical and spatial work-ing memory after a 12 week trial of a ginkgo/ginsengcombination [47]. A similar 30 day trial on adults [48]demonstrated significant improvements in workingmemory (along with processing speed and other aspectsof executive function) following treatment with 120 mgGinkgo biloba in comparison to placebo. Compared tothe current pilot study, these previous studies used lar-ger samples (N = 16 vs. N = 61–256) and different treat-ment doses (120 mg vs. up to 320 mg) for longerperiods (1 week vs. 4–12 weeks), suggesting that the ef-fect of SLT could be much greater given an increase inthese parameters. In the current study, no effect of SLTwas found on other Compass measures including Imme-diate and Delayed Word Recall, Word Recognition,Simple and Choice Reaction Time, Numeric WorkingMemory, Corsi Block Span, Picture Recognition, FaceRecognition, Serial Subtraction, and the RVIP task, oron the mood and alertness scales.

From the visual and auditory oddball tasks, five ERPcomponents were identifiable from each of the unre-stricted temporal PCAs: N1, P2, N2, P3a, and P3b. Vis-ual N1, N2, and P3b, and auditory N2, P3a, and P3bwere all larger to targets than nontargets. These findingsare broadly similar with previous oddball studies [49–54]. As the purpose of this study was to evaluate the ef-fects of SLT, these target/nontarget differences togetherwith the components that were not sensitive to treat-ment with SLT (visual N1, P2, N2, P3a, and P3b, andauditory P2, N2, and P3b) will not be discussed further.Target N1 was smaller following SLT compared to

placebo (from baseline to post-treatment) than nontargetN1. This is a novel finding that has not been reportedelsewhere in the literature. To the best of our know-ledge, only one other study has examined changes in N1amplitude after treatment with any SLT constituents. Inthat study [53], no changes in auditory oddball N1, P2,N2, or P300 amplitudes were reported after acute andchronic doses of Ginkgo biloba. The N1 componentelicited in the current study had a strong fronto-centraltopography and latency (132 ms) suggestive of N1Component 1 [54]. This component is generated in thesupratemporal plane of the primary auditory cortex [55],and it is thought to facilitate the conscious perception ofauditory stimuli [50]. A reduction in amplitude indicatesless activation in these regions. Although it is difficult tospeculate about any functional significance of thistreatment-related change, findings might reflect moreefficient attentional processing of auditory information.Auditory P3a amplitudes trended towards being

larger following SLT than placebo for targets comparedto nontargets; another novel finding. P3a, is elicited toattention-capturing stimuli [56, 57] and is thought torelate to working memory processes [58], with evidencefrom lesion studies suggesting that its neural generatorsare located in the frontal lobe, hippocampus, and thal-amus [59; for a review see 60]. Speculatively, and whenviewed in conjunction with the Compass test findings, thisSLT-related enhancement in P3a amplitude, may repre-sent increased working memory activation. It should alsobe noted that an analysis of P3a has not been reported insimilar herbal medicine work as most studies quantifycomponent amplitudes using baseline-to-peak measures.It is important to investigate overlapping componentsusing techniques such as PCA (as done in the currentstudy) in order to fully understand the (often subtle) ef-fects of various interventions. There were no SLTtreatment-related effects on the other visual and auditoryERP component amplitudes.The topographic distribution for each of the EEG bands

was in line with previous work examining resting condi-tion amplitudes [61]. Delta and theta were largest at themidline, and alpha and beta were both maximal parietally.

Table 6 Frequency of adverse events during treatment cyclesand washout period

DuringActiveCycle

During PlaceboCycle

DuringWashout

Tiredness 3 2 3

Headaches 2 1 1

Loose Stools 1 1 0

StomachPain

1 0 0

Back Pain 1 0 0

Poor Sleep 0 1 0


Typical condition-related changes in amplitudes were ap-parent with larger amplitudes for eyes closed than eyesopen for theta and alpha bands; a pattern of resultsbroadly in line with other work [62–63]. Treatment withSLT did not have an effect on resting EEG activity.Mean aortic and peripheral pulse pressure, and resting

HR did not show any changes with SLT treatment. Thisis not surprising given that the current study recruitedhealthy adults, and special care was taken to ensure thatolder participants, who are at increased risk of cardio-vascular disease, had a full blood count that was withinnormal limits.

Limitations and future directionsThis was the first study to assess SLT, a formula with aunique combination of three herbs, in a healthy cohort.Compared to this study, previous work [47, 48] usingGinkgo biloba and/or Panax ginseng found significantimprovements in a range of executive functions, such asepisodic memory, in addition to improved mood andarousal (for a review see [64]). Those studies used largersample sizes (N = 61–256), longer interventions (4–12weeks), and larger treatment doses (up to 320 mg per day)than the current study. Given the substantial preclinicalwork showing the potential benefits of SLT, and theincrease in therapeutic effects due to synergism, furtherresearch in a larger cohort is needed, with increases in theparameters mentioned above.Future work is also required to replicate the novel N1

and P3a amplitude findings, and should also includelatency analyses. Previous research [52, 65] has reportedchanges in latency, rather than amplitude, however,latency analyses are not possible with temporal PCA.Future work could complement PCA analyses with Resi-due Iteration Decomposition (RIDE) analysis, which useslatency variability to estimate single trial latencies with ahigh degree of precision [66–68]. A study combiningthese analyses would be able to examine any treatment-related changes in ERP components effectively.As with the neurocognitive measures, the dose and

treatment length of SLT were probably too small to affectcardiovascular parameters in healthy adults. Further, thereis some evidence suggesting that acute, rather thanchronic, administration of ginkgo may produce largereffects. For instance, another study employed radial pulsewave analysis to measure reflection, stiffness, and periph-eral augmentation indices and reported improvements inthe stiffness index 2 h after treatment [69]. Future workcould examine both the acute and chronic effects of SLTon cardiovascular function in healthy adults.

ConclusionsAlthough the observed effects of SLT were small, find-ings indicate that SLT has the potential to improve

working memory performance in healthy adults. A largersample size, and possibly a higher dose of SLT over alonger period are needed to extend upon these results. Adose escalation study to determine the appropriate dos-age for cognitive benefits is recommended. The possiblebenefits of SLT should also be explored in healthy olderadults, and individuals with mild cognitive impairment.

AbbreviationsSLT: Sailuotong; EEG: Electroencephalograph; ERP: Event-related potential;CHM: Chinese Herbal Medicine; AChE: Acetylcholinesterase; NMDA: N-methyl-D-asparate; ADAS-cog: Alzheimer’s Disease Assessment Scale cognitive subscale;SPECT: Single Photon Emission Computed Tomography; HR: Heartrate; RVIP: RapidVisual Information Processing; VAS: Visual Analogue Scale; RT: Response Time;PCA: Principal Components Analysis.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsGZS conducted the analyses and wrote the manuscript draft. AY carried outthe study and collected the data. DAC was involved in the design of the EEGcomponent of the study, conducted preliminary post-processing of EEG andERP data and critically reviewed the drafted manuscript. FMD wrote the scriptsused for analysis of EEG and ERP data. JL provided relevant information on theintervention and was involved in the design of the study. AP, ABS, and CSassisted in setting up the laboratory equipment and data analyses. DHCinitiated the study, supervised the study design and the data collectionprocess, and critically reviewed the drafted manuscript. All authors readand approved the final manuscript.

AcknowledgementsThe study was funded by Western Sydney University. The authors would liketo acknowledge Shineway Pharmaceutical Group, China for their kindcontribution of the SLT and placebo capsules needed for the study, and tothank Drs Ben Colagiuri and Rong Luo for their assistance in recruitment andassessment of participants.

Author details1National Institute of Complementary Medicine, and School of Science andHealth, Western Sydney University, Penrith NSW 2751, Australia. 2Centre forPsychophysics, Psychophysiology, and Psychopharmacology; Brain &Behaviour Research Institute; and School of Psychology, University ofWollongong, Wollongong NSW 2522, Australia. 3Xiyuan Hospital, ChinaAcademy of Chinese Medical Sciences, Beijing 100091, China. 4Centre forHuman Psychopharmacology, Swinburne University of Technology,Hawthorn VIC 3122, Australia. 5Illawarra Health & Medical Research Institute,University of Wollongong, Wollongong NSW 2522, Australia.

Received: 20 December 2014 Accepted: 7 January 2016

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AbstractBackgroundMethodsResultsConclusionsTrial registration

BackgroundMethodsInclusion criteriaTreatmentsDesignMaterials and apparatusCognitive test batteryElectroencephalograph (EEG)Cardiovascular measures

ProcedureEEG data extraction and quantification

Statistical analysesCognitive and cardiovascular measuresEEG and ERPs

ResultsCognitive functionERP componentsEEG spectral bandsCardiovascular measuresAdverse effects

DiscussionLimitations and future directions

ConclusionsAbbreviationsCompeting interestsAuthors’ contributionsAcknowledgementsAuthor detailsReferences

Documents

The effect of Sailuotong (SLT) on neurocognitive and ......dementia [13]. For example, acetylcholinesterase (AChE) inhibitors (e.g., donepezil) act on the enzyme which breaks down